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The genetic etiology of gestational diabetes mellitus (GDM) was suggested to overlap with type-2 diabetes(T2D). Transcription factor 7-like 2 (TCF7L2) and Proprotein Convertase Subtilisin/Kexin type 2 (PCSK2) are T2D susceptibility genes of the insulin synthesis/processing pathway. We analyzed associations of TCF7L2 and PCSK2 variants with GDM risk and evaluated their potential impact on impaired insulin processing in an eastern Indian population. The study included 114 GDM (case) and 228 non-GDM pregnant women (control). rs7903146, rs4132670, rs12255372 of TCF7L2, and rs2269023 of PCSK2 were genotyped by PCR-RFLP, and genotype distributions were compared between case and control. Fasting serum proinsulin and C-peptide levels were measured by ELISA and the Proinsulin/C-peptide ratio was considered an indicator of proinsulin conversion. Significantly higher frequency of risk allele (T) of rs12255372 (p = 0.02, OR = 2.0, 95%CI = 1.11–3.64) and rs4132670 (p = 0.002, OR = 2.26, 95%CI = 1.32–3.87) of TCF7L2 was found in GDM cases than non-GDM controls; TT genotype was associated with significantly increased disease risk. In rs7903146 (TCF7L2) and rs2269023 (PCSK2), although the frequency of risk allele (T) was not significantly higher in cases than controls, an association of TT for both variants remained significant with higher GDM risk in the recessive model. Increased serum pro-insulin and proinsulin:c-peptide ratio was found in GDM than non-GDM women and the phenomenon showed significant association with careers of risk alleles for TCF7L2 variants. In conclusion, TCF7L2 and PCSK2 variants are related to GDM risk in the studied population and hence may serve as potential biomarkers for assessing the disease risk. TCF7L2 variants contribute to impaired insulin processing. [ABSTRACT FROM AUTHOR]

Aims Prevalence of gestational diabetes mellitus (GDM) may vary across a country like India. Risk factors and disease-pathogenesis were also not fully elucidated. This study aimed to examine prevalence of GDM among pregnant women visiting antenatal clinic of a tertiary-care hospital of Kolkata, India; possible mechanism of disease pathogenesis and potency of associated parameters as disease biomarkers were also explored. Methods 735 pregnant women were screened for GDM according to DIPSI (Diabetes in Pregnancy Study Group India) guideline and risk-factors were analyzed. Case-control study was conducted with 114 GDM and 114 matched non-GDM control. Blood sample was collected before glucose load for complete blood count, measurement of reactive oxygen species (ROS) and assessment of DNA damage. Results Prevalence of GDM was found to be 17.2%(127/735). Maternal age, diabetic family history and acanthosis nigricans seemed to be important risk factors. Total ROS, lymphocyte DNA damage (measured by comet-assay) and some inflammatory hematological parameters were significantly higher in GDM compared to control. ROS, comet-tail DNA%, WBC, neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV) were established as independent determinants of disease condition after adjustment for pre-gestational body mass index. In receiver operating characteristic analysis, ROS>155.7 arbitrary fluorescent unit, NLR>2.12 and MPV>11.05 fL showed 82.5 & 98.2%, 71.9 & 84.2% and 71.9 & 82.5% sensitivity & specificity respectively in disease prediction. Conclusions Prevalence of GDM seemed to be high in Kolkata on Indian scenario. Oxidative-stress, related DNA-damage and inflammation seemed to have important contribution in pathogenesis of GDM independent of obesity. ROS, NLR and MPV with respective cut-off scores might be used as diagnostic and prognostic biomarkers for better management of the disease. [ABSTRACT FROM AUTHOR]